The subject matter disclosed herein relates to inhibitors of cysteine cathepsins. Cysteine cathepsins are an important family of enzymes that are implicated in a variety of human diseases. Consequently they are considered key therapeutic targets for drug development. Cathepsin L is an important member of this family which is found to be overexpressed in a variety of human cancer and osteoporosis. Aberrant expression and activation of cathepsin L has been implicated in many forms of human diseases. These include highly invasive cancer, cardiovascular, lung, immune, and metabolic disorders. Cathepsin L is notably overabundant in a variety of metastatic cancer cells, including cancers from glial, breast, melanoma, and myeloma origins. In glial cells, Cathepsin L overexpression can lead to progression from astrocytoma to high-grade malignant glioblastoma, a most deadly form of brain tumor. Importantly, selective inhibition of cathepsin L abrogates human brain cell invasion, and promotes apoptosis. Cathepsin L can promote metastatic behavior by efficiently degrading and hydrolyzing various components of extracellular matrix (ECM), such as laminin, fibronectin, and collagen IV. These studies strongly indicate that cathepsin L could activate signaling pathways relevant to invasion in metastatic cancer. Inhibitory perturbation in highly invasive cancer types is therefore considered an attractive strategy for anti-cancer drug development. Thus, inhibition of cathepsin L with suitable small molecule inhibitors is desired for development of suitable chemotherapeutic agents. There is also a significant gap in understanding cathepsin L biology. Potent, selective, and cell permeable small molecule inhibitors, and probes are desired so they can be utilized to understand the undocumented function of this important enzyme. Unfortunately, highly selective, potent and cell permeable inhibitors and probes remain scarcely available for cathepsin L.
The discussion above is merely provided for general background information and is not intended to be used as an aid in determining the scope of the claimed subject matter.